Methamphetamine (METH) alters monoaminergic (e.g. dopaminergic; DA) systems leading to a refractory dependence and psychotic, violent and criminal behaviors. Because no FDA-approved medications are available to treat METH dependence, the National Institute on Drug Abuse (NIDA) has encouraged research of CNS systems that contribute to METH dependence to identify novel therapeutic strategies. Thus, others and we study how neurotensin (NT) influences the function of DA basal ganglia and limbic pathways and how it contributes to the effects of METH. NT is a neuropeptide associated with both the indirect (D2-regulated) and direct (D1-regulated) feedback pathways to the nigrostriatal DA projection, with similar, but less well delineated, feedback arrangements in limbic structures. Overall stimulation of these NT systems reduces DA-mediated behaviors and counteracts overactive DA pathways. Consequently, these NT pathways have been classified as natural neuroleptic systems and NT agonists have been suggested by NIDA as possible medications for treating drug abuse. It has been reported that not only does NT mitigate DA responses, but its pathways are reciprocally regulated by DA with stimulation of D2 and D1 receptors causing opposing decreases and increases of NT tissue levels, respectively, in both basal ganglia and limbic brain regions. Relevant to the present proposal are findings that similar NT responses to non-contingent low and high doses of METH are principally mediated by these same D2 and D1 receptors, respectively. In order to determine the clinical relevance of these findings, we used METH self-administration (SA) models based on contingent lever pressing to obtain METH infusion and observed that: (i) the NT agonist, PD149163 blocks METH SA while not substituting for METH nor being self-administered per se; (ii) PD149163 blocks lever pressing during maintenance (i.e., operant responses associated with stable METH SA), beginning of extinction (i.e., elimination of lever pressing when no longer linked to METH infusion) and reinstatement (the lever- pressing response of rats to a METH trigger given after extinction); (iii) endogenous NT systems linked to D2 and D1 mechanisms, differentially contribute to behaviors associated with extinction and maintenance, respectively. Based on these findings, we will examine behavioral and basal ganglia and limbic NT/DA responses to test the hypothesis that endogenous NT systems have differential roles in extinction, maintenance and reinstatement of METH SA, by achieving the following: Specific Aim A: Determine the role of NT systems and related D2 receptors on extinction of METH- seeking behavior (i.e., reduced lever pressing). Specific Aim B:Determine the role of NT systems and related D1 receptors on METH SA maintenance. Specific Aim C: Determine the effect of METH SA reinstatement on NT systems. PUBLIC HEALTH RELEVANCE: Methamphetamine (METH) abuse inflicts severe personal and societal harm. Our extensive studies have suggested that basal ganglia and limbic neurotensin (NT) systems are sensitive to dopamine (DA) D1 and D2 regulation and in turn through inhibitory feedback mechanism help to influence the response in rats to non- contingent METH treatment. To determine the clinical relevance of these findings to METH abuse, we are studying the impact of METH self-administration (contingent on lever pressing) on the NT pathways associated with the dorsal striatum and nucleus accumbens. We have determined that NT systems respond in contrasting ways to maintenance, extinction, and reinstatement in our self-administration METH model and that endogenous NT systems specifically contribute to the elimination of lever pressing during extinction as well as a lack of lever pressing in a minoriy of non-responding rats during maintenance. Because of these findings we propose to test the specific hypothesis that endogenous NT systems have differential roles in the extinction, maintenance, and reinstatement of METH self-administration.